Conception, Synthesis and In silico Assessment of New Morpholine-Containing Compounds Against Human Legumain and Cholinesterase Enzymes

The convenient syntheses of new morpholine derivatives bearing nitrile, amine, ester, phosphonate, or ketone functions are described. All compounds were successfully synthesized in high yields starting from easily available reactants through a two-step process involving a Mannich reaction followed by Michael addition reaction under mild conditions. The chemical structures of novel synthesized morpholine-based compounds were assessed by 1 H, 13 C, 31 P nuclear magnetic resonance (NMR), and high‐resolution mass spectrometry (ESI-HRMS). Based on previous works on biological activities of this class of morpholine-containing compounds, an in silico evaluation was performed to investigate the potential inhibitory activity of the synthesized products against human legumain (AEP) and cholinesterases (AChE and BuChE) enzymes. The molecular docking study suggests that all compounds interact with the three enzymes with moderate to high affinity. Derivative 14 , among the list ( 11–24 ), exerted the best binding affinity towards the three enzymes, compared to the corresponding reference products. Additionally, predicted ADMET properties indicated that most compounds displayed promising pharmacokinetic and drug-likeness properties.